The present invention relates to novel derivatives of cyclopropanecarboxylic acid, pharmaceutical compositions comprising same and uses thereof in a variety of therapeutic applications.
Epilepsy, also referred to as a seizure disorder, is a chronic disorder of the central nervous system (CNS), characterized either by recurrent and unprovoked episodic loss of attention or sleepiness or by severe convulsions with loss of consciousness called seizures or fits. The seizures are considered as transient symptoms which are attributed to irregular immoderate or coincident neuronal activity in the brain. This incurable yet typically therapeutically controlled medical condition affects about 0.5% of the population, whereas about 1.5-5.0% of the population may have a seizure in their lifetime at any age.
Prolonged seizures may lead to the development of Status epilepticus (SE), which is a life threatening cerebral state of a persistent seizure. SE can be defined broadly as one continuous seizure or a series of recurrent seizures wherein the subject does not regain consciousness between seizures for longer than 30 minutes. It is believed that 5 minutes are sufficient to cause irreparable damage to the neurons, and in SE cases seizures are unlikely to terminate spontaneously by that time. In a subject known to suffer from epilepsy, SE can be brought about or be aggravated by poor compliance to treatment (adherence to medication regimen), alcohol withdrawal and/or metabolic disturbances. As a primary presentation it may indicate a brain tumor or abscess. SE was also reported to be caused by various nerve agents (organophosphates) such as sarin, VX and soman.
The treatment of epilepsy typically consists of oral administration of anti-convulsants or antiepileptic drugs (AEDs). This symptomatic treatment is aimed at reducing the number and severity of future seizures. The efficacy of AEDs depends on the patient's response to any particular AED, which in turn is selected according to the type and severity of the seizure. Some epileptic patients are known to respond well to one AED and may respond poorly or even worsen the condition by others. When the epileptic condition seems not to respond to the use of AEDs, it is referred to as “refractory epilepsy”, which is typically treated by brain surgery to remove the abnormal brain cells that are causing the seizures, or by a vagal nerve stimulator, which is implanted in the chest, which helps reducing the number of seizures.
Currently, four major AEDs are used for the treatment of epilepsy: phenytoin (marketed as Dilantin® in the USA and as Epanutin® in the UK); carbamazepine (sold under the brand-names Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Tegretol, Telesmin, Timonil); phenobarbital (also known as phenobarbitone or Luminal®) and valproic acid (VPA).
However, only about 75% of epileptic patients respond to the presently used AEDs. Furthermore, these widely used AEDs have been shown to cause some rare and severe adverse side effects such as teratogenicity that limit their use. Therefore, in a significant part of epileptic cases, and particularly when these AEDs are administered repetitively as the main treatment for chronic epileptic conditions, the adverse effects associated therewith upset the balance of beneficial-to-harmful effect, and leaves the patient with little or no salvation.
Status epilepticus is typically treated with benzodiazepines such as diazepam, clonazepam, lorazepam phenobarbital, phenytoin and lorazepam. Phenytoin and its prodrug fosphenytoin as well as other hydantoin derivatives are also used to treat SE, and are typically co-administered with a benzodiazepine phenobarbital or barbiturate. Barbiturates such as phenobarbital, secobarbital, thiopental or pentobarbital, are still used today to treat SE if benzodiazepines or the hydantoins are not an option, primarily by induction of a barbituric coma. In that respect of coma-causing agents, general anesthetics such as propofol and lidocaine are used where barbiturates are ineffective or cannot be used for some other reason.
Valproic acid (VPA, Compound I, see FIG. 1) is a broad-spectrum antiepileptic and CNS active agent and one of the abovementioned AEDs which is still in use as an anticonvulsant and mood-stabilizing drug in the treatment of epilepsy [1]. Valproic acid has also been used in the treatment of other CNS-related conditions such as bipolar disorder [1], neuropathic pain, myoclonus, schizophrenia and for migraine prophylaxis [2, 3].
VPA is believed to act through a combination of mechanisms: as a membrane stabilizer, via GABA transaminase inhibition which results in enhanced GABA signaling, and as a serotonergic inhibitor which reduces NMDA-receptor mediated glutamate excitation [5-7]. In principle, such multilevel action is highly advantageous, promising improved efficacy with reduced side effects. Nonetheless, the clinical use of VPA is severely limited by two rare, yet potentially life-threatening side effects, teratogenicity and hepatotoxicity, which restrict its utilization in women of child bearing age and in children. While VPA's teratogenicity is associated with the parent compound [8], its hepatotoxicity results from biotransformation into hepatotoxic metabolites with a terminal double bond, specifically 4-ene-VPA [9].
Extensive efforts have therefore been directed towards therapeutically active derivatives of VPA which exhibit improved activity and/or reduced side effects.
Therapeutically active derivatives of VPA include the salt sodium valproate which is used in anticonvulsant formulations, and valproate semisodium, which is used as an anticonvulsant and a mood stabilizer. A homologue of VPA wherein one of the alkyl chains is three carbons longer, arundic acid ((R)-(−)-2-propyloctanoic acid, also known as ONO-2506), is currently under clinical development for the potential treatment of stroke, as well as of other neurodegenerative diseases including amytrophic lateral sclerosis (ALS), Alzheimer's disease and Parkinson's disease [4].
A series of VPA-amide analogue and derivatives thereof was developed via a series of structure (pharmacokinetic/pharmacodynamic) activity relationship studies, and were found to exhibit improved anticonvulsant activity while avoiding teratogenicity and hepatotoxicity [10-13]. Some of these VPA amide derivatives were also active in animal models of neuropathic pain [14, 15] and bipolar disorder [16, 17].
2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA, Compound II, see FIG. 1) is a cyclic analog of VPA which was shown to possess weak anticonvulsant activity; however the toxic effect of TMCA overshadows its beneficial activity as an anticonvulsant [10, 14].
U.S. Patent Application having Publication No. 20060004098 teaches the use of various VPA-like and TMCA derivative compounds for treating neuropathic pain, migraine, psychiatric disorder and/or neuronal degeneration.
U.S. Pat. No. 5,880,157 discloses ester derivatives of TMCA as well as processes for preparing same and pharmaceutical preparations comprising the same, particularly intended for the treatment of epilepsy.
U.S. Patent Application having Publication No. 20050131069 teaches derivatives of N-hydroxyalkyl-tetramethylcyclopropane carboxamide, pharmaceutical compositions containing same, methods for their preparation, and use thereof for the treatment of epilepsy, neurological, affective and psychotic disorders and for the treatment of pain and migraine.
U.S. Patent Application having Publication No. 20060148861 teaches derivatives of 2,2,3,3-tetramethylcyclopropane carboxamide, pharmaceutical compositions containing same and uses thereof for treating psychotic disorders, neurodegenerative diseases, epilepsy and pain. According to the teachings of this patent application, the corresponding amide of TMCA, 2,2,3,3-tetramethylcyclopropanecarboxamide (Compound III, see FIG. 1) and its N-methyl derivative N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (Compound IV, see FIG. 1) were found to possess a broad spectrum anticonvulsant activity while not evoking teratogenic and probably hepatotoxic effects [10, 11]. In following studies, 2,2,3,3-tetramethylcyclopropylcarbonyl urea (Compound V, see FIG. 1) was found to be the most promising compound, having a protective index, namely TD50-to-ED50 ratio of 18.5 in the maximal electroshock (MES) tests, compared to 1.6 measured for VPA [13].
Unlike VPA, TMCA (Compound II) and the tetramethylcyclopropyl amide analogues of VPA, namely Compounds III, IV and V, possess two quaternary carbons at the β-position relative to the carbonyl and hence, as opposed to VPA, these derivatives cannot undergo bio-transformation into hepatotoxic metabolites with a terminal double bond [10-13]. These compounds were found more potent than VPA as therapeutics for neuropathic pain in spinal nerve ligated rat models [14]. The most promising analogue, Compound IV, was further found to be non-neurotoxic, non-sedative and equipotent to GABApentin (Neurontin®), a currently leading drug for neuropathic pain treatment.
U.S. Pat. No. 6,960,687 discloses derivatives of N-(hydroxy-substituted)-2,2,3,3-tetramethylcyclopropanecarboxamide, as well as pharmaceutical compositions containing same, methods for their preparation, and use thereof for the treatment of epilepsy, neurological, affective and psychotic disorders and for the treatment of pain and migraine.
The N-methoxy derivative of TMCA, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (Compound VI, see FIG. 1) and the 1,3,4-thiadiazole-2-sulfonamide derivative of TMCA, N-(1,3,4-thiadiazole-2-sulfonamide)-2,2,3,3-tetramethylcyclopropanecarboxamide (Compound VII, see FIG. 1) were shown to possess promising anticonvulsant activity in the maximal electroshock (MES) and in the subcutaneous metrazol injected (scMet) induced seizure model in rats. In these studies, Compound VI exhibited ED50 values of 57 mg/kg MES tests and 9.8 mg/kg in scMet tests, as measured in seizure model in rats injected intraperitoneally. This compound was found less teratogenic than VPA [Okada et al., Birth Defect Research (Part B) 77:227-233 (2006)]. Compound VII exhibited good MES-ED50 values of 17 mg/kg in mice models injected intraperitoneally, and 9.2 mg/kg in orally treated rat models, and was found none-neurotoxic at 500 mg/kg doses. However, analysis in a mouse model for VPA-induced teratogenicity showed that Compound VII is teratogenic (unpublished results).
In recent studies comparing α-fluorinated and non-fluorinated VPA, it was shown that α-fluorination leads to a chemical structure with a greatly reduced adverse hepatotoxic activity [18, 19]. Other works, such as described in Hoffmann, H. M. R. et al., [Ang. Chem., 1982, 94(1), 79-80]; and Wulff, J. M. et al., [Ang. Chem., 1985, 97(7), 597-9]; report the preparation of a few α-bromo-derivatives of 2,2,3,3-tetramethylcyclopropane-carboxylic acid. Likhotvorik, I. et al., [J. Am. Chem. Soc. 2001, 123, 6061-6068]; Tippmann, E. M. et al., [Org. Lett., 26(5), 2003]; Tippmann, E. M. et al., [J. Am. Chem. Soc., 126(9), 18, 2004, 5751]; and Martinu, T. et al., [J. Org. Chem., 2004, 69, 7359-7362], report the preparation of a few α-fluoro, α-bromo and α-chloro-derivatives of 2,2,3,3-tetramethylcyclopropane-carboxylic acid, yet the therapeutic activity thereof was neither described nor suggested and tested.
Hence, although massive studies have been conducted regarding therapeutically active VPA derivatives, efficacious derivatives which overcome the limitations associated with VPA therapy have not been uncovered yet. While 2,2,3,3-tetramethylcyclopropane carboxamides were found as promising candidates in this respect, a need still remains for derivatives thereof that would exhibit an improved effect.
There is thus a widely recognized need for, and it would be highly advantageous to have novel derivatives of cyclopropylcarboxy compounds, devoid of the above limitations.